The goal of this revised grant continues to be testing several hypotheses about neurotropic factor somatic gene transfer into the septohippocampal system. These studies use adeno-associated virus (AAV) recombinant vectors containing the neuron specific enolase (NSE) promoter to drive expression of nerve growth factor (NGF) or brain derived neurotrophic factor (BDNF). Initial studies demonstrating robust expression of the marker gene green fluorescent protein (GFP) in septum and hippocampus for extended intervals after transduction have been extended to observations about trophic factor expression, levels of cholinergic markers and trk-receptor density in this pathway. Expression is neuro-specific in each region studied. Some degree of tropism for subpopulations o neurons is also apparent in hippocampus, though not so in septum. Our grant proposes to test: 1) whether there are dose- and time-dependent expressions of NSE-driven GFP expression in different hippocampal and septal neurons: 2) if ectopic BDNF and NGF expression in intact septum and hippocampus elevates cholinergic and trk markers without altering GABAergic activity; 3) if BDNF and NGF gene transfer into septum preferentially protects axotomized cholinergic neurons in a manner not seen with either similar gene transfer in hippocampus or with GABAergic neurons: 4) whether both hippocampal and septal trophic factor gene transfer can improve memory-related behaviors in animals receiving partial fornix lesions; 5) whether age-related deficits in memory-related behaviors and acetylcholine release can be overcome with septal NGF or BDNF gene transfer; and 6) if aging interferes with the expression of transgenic NGF more than that of BDNF, as predicted from studies of endogenous trophic factor regulation during senescence. These studies may lead eventually to gene therapy trials for conditions associated with septohippocampal cholinergic deficits such as Alzheimer's disease.